Heteroaryl compounds and their use

a technology of heteroaryl compounds and compounds, applied in the field of heteroaryl compounds, can solve problems such as diarrhea, peripheral nerve damage, side effects,

Active Publication Date: 2019-11-07
MINORYX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The present disclosure is related to the discovery that heteroaryl compounds represented by formula (I) are capable of binding to mutated β-glucocerebrosidase and are thus useful in the treatment or prevention of a lysosomal storage disease, such as Gaucher's disease.

Problems solved by technology

While ERT may be effective in reducing and reversing the clinical symptoms of the disease, it is very costly.
While SRT may be effective for some patients, it is associated with side effects, including weight loss, diarrhea, tremors, and peripheral nerve damage.

Method used

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  • Heteroaryl compounds and their use
  • Heteroaryl compounds and their use
  • Heteroaryl compounds and their use

Examples

Experimental program
Comparison scheme
Effect test

example 1

6-((Methyl(phenyl)amino)methyl)-N2-(p-tolyl)-1,3,5-triazine-2,4-diamine

[0322]

[0323]Yield: 9%.

[0324]HPLC-MS [M+H]+: 321; Rt=2.72 min (Method C).

[0325]1H NMR (400 MHz, CDCl3) δ: 7.28 (s, 2H), 7.15 (ddd, J=7.3, 5.9, 2.3 Hz, 2H), 7.00 (d, J=7.4 Hz, 2H), 6.84 (s, 1H), 6.71 (dd, J=8.8, 0.9 Hz, 2H), 6.65 (td, J=7.3, 1.0 Hz, 1H), 5.04 (s, 2H), 4.26 (s, 2H), 3.07 (s, 3H), 2.24 (s, 3H).

example 2

N2-(4-Methoxyphenyl)-6-((methyl(phenyl)amino)methyl)-1,3,5-triazine-2,4-diamine

[0326]

[0327]Yield: 6%.

[0328]HPLC-MS [M+H]+: 337; Rt=2.43 min (Method C).

[0329]1H NMR (400 MHz, CDCl3) δ: 7.24 (d, J=20.0 Hz, 2H), 7.18-7.13 (m, 2H), 6.79 (s, 1H), 6.75 (s, 2H), 6.72-6.68 (m, 2H), 6.67-6.62 (m, 1H), 5.05 (s, 2H), 4.25 (s, 2H), 3.72 (s, 3H), 3.05 (s, 3H).

example 3

N2-β-Methoxyphenyl)-6-((methyl(phenyl)amino)methyl)-1,3,5-triazine-2,4-diamine

[0330]

[0331]Yield: 21%.

[0332]HPLC-MS [M+H]+: 337; Rt=2.65 min (Method C).

[0333]1H NMR (400 MHz, CDCl3) δ: 7.19 (d, J=2.1 Hz, 1H), 7.17-7.13 (m, 2H), 7.10 (t, J=8.5 Hz, 1H), 6.97 (s, 1H), 6.93 (dd, J=8.2, 1.4 Hz, 1H), 6.69 (dt, J=3.5, 1.8 Hz, 2H), 6.64 (tt, J=5.0, 2.5 Hz, 1H), 6.57-6.51 (m, 1H), 5.16 (s, 2H), 4.26 (s, 2H), 3.70 (s, 3H), 3.07 (s, 3H).

General Procedure III

[0334]

[0335]To a stirred solution of the appropriate biguanide hydrochloride salt (ex: p-tolylbiguanide) (1.0 eq) in methanol (2.4 mL / mmol) was added sodium methoxide (1.0 eq, 25 wt % in methanol) at room temperature and it was stirred for 30 min. The appropriate ester was added to the reaction mixture (ex: ethyl N-benzyl-N-methylglycinate) (1.2 eq) and heated to 70° C. for 18 h. After reaction completion, the reaction mixture was poured into cold water and the organic product was extracted with ethyl acetate. Organic extracts were dried ove...

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Abstract

The application is directed to compounds of formula (I): and their salts and solvates, wherein R1, R2, R3, A1, A2, A3, and n are as set forth in the specification, as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of a lysosomal storage disease, such as Gaucher's, and other diseases or disorders that are synucleinopathies.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims priority to European Application No. EP16382672.0, filed on Dec. 29, 2016, the entirety of which is incorporated by reference herein.FIELD OF THE DISCLOSURE[0002]The present disclosure is related to heteroaryl compounds, and especially pyridyl, pyrimidinyl, and triazinyl compounds, new processes for their preparation, and the use of the heteroaryl compounds in the treatment and / or prevention of lysosomal storage disorders in a patient, such as Gaucher's disease. The present disclosure is also related to the use of the heteroaryl compounds described herein in the treatment and / or prevention of other medical disorders in a patient, such as, for example, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycyctic kidney disease, type 2 diabetes, open angle glaucoma, multiple sclerosis, or multiple myeloma.BACKGRO...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/06C07D239/49C07D401/12C07D405/12C07D403/06C07D251/18A61P43/00
CPCC07D401/06C07D239/49C07D401/12A61P43/00C07D403/06C07D251/18C07D405/12C07D239/48C07D251/48C07D213/36A61P25/00A61P25/16A61P25/28
Inventor GARCÍA COLLAZO, ANA MARIABARRIL ALONSO, XAVIERCUBERO JORDÀ, ELENAREVÉS VILAPLANA, MARCROBERTS, RICHARD SPURRING
Owner MINORYX THERAPEUTICS
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